The control and cure of cancer represents one of our most challenging health problems. The treatment of cancer can be approached by several modes of therapy including surgery, radiation, chemotherapy or a combination of any of these treatments. Chemotherapy continues to be an indispensable therapy for inoperable or metastatic forms of the disease.
The selection of natural compounds, or the synthesis of new compounds having effective anticancer activity is complicated by the still limited knowledge of cancer cell biology and biochemistry. Therefore, development of new effective anti-tumor agents will remain heavily dependent on screening compounds to discover novel compounds having cytotoxic activity. Preferably, such compounds exhibit enhanced cytotoxicity against tumor cells relative to their cytotoxicity to normal cells.
Natural products have a history of providing novel, clinically useful anticancer drugs. Many active natural products have also served as prototypes for the development of new analogs of clinical and preclinical importance. Some specific examples are the Vinca alkaloids (vincristine, vinblastine, vindesine and vinorelbine), podophyllotoxins etoposide and teniposide), taxanes (taxol, taxotere), camptothecins (10-hydroxycamptothecin, 9-dimethylaminomethylcamptothecin, 9-aminocamptothecin and CPT-11), homoharringtonine, adriamycin, daunomycin, bleomycin, mitomycin, idamycin, plicamycin and dactinomycin. It is clear that natural products will continue to be important sources of novel anticancer agents. However, key to the success of novel antitumor drug development programs is the initial identification of potential antitumor agents.
The mouse L1210 leukemia cell line was initially the preferred model system used for screening natural compounds for antitumor activity. However, the P388 murine leukemia system was found to be more sensitive and predictive than L1210 leukemia system, and has been used as primary screen during the past decade. Systematic screening for compounds exhibiting toxicity to these two leukemia cell lines has resulted in the isolation of a large number of active natural products. However, the anticancer activities of these compounds were predominantly in leukemia, lymphoma and a few rare tumors. Low clinical efficacy, or the lack of clinical efficacy of known chemotherapeutics against slower growing solid tumors, is a serious concern.
It has been recognized that the use of a single antileukemia screening system could bias the end results and lead to the isolation of compounds only active in the treatment of fast growing tumors. In addition, the use of a single antileukemia screening system may not detect novel compounds with high specificities for particular cell lines. It is also likely that many novel compounds with possible anti tumor activity have remained undetected by the less sensitive in vivo models due to the low concentrations at which many active natural products occur.
Considering the diversity of tumors in terms of cell type, morphology, growth rate and other cellular characteristics, the U.S. National Cancer Institute (NCI) has developed a "disease-oriented" approach to antitumor activity screening (M. R. Boyd, in "Principle of Practice of Oncology" J. T. Devita, S. Hellman, S. A. Rosenberg (Eds.) Vol. 3, PPO Update, No. 10, 1989). This in vitro prescreening system is based on the measurement of antitumor cytotoxicity against human tumor cell line panels consisting of approximately 60 cell lines of major human tumors (including leukemia and slower growing tumor cells such as lung, colon, breast, skin, kidney, etc.). The most important advantage of the new in vitro screening panels is the opportunity to identify compounds that are selectively more cytotoxic to cells of slowly growing solid tumors than to rapidly growing leukemia cells.
Thiophenes are sulfur containing heterocyclic compounds that are distributed widely among the species of the Asteraceae (Compositaie) family, including many species with known medicinal uses. The natural thiophene compounds are thought to play an important role in the chemical defense of plants against herbivorous insects and other pests. Natural thiophenes have been previously described as having cytotoxic activities upon exposure to long wavelength ultraviolet light. Photochemical studies suggest that thiophene phototoxicity is based primarily on the production of toxic singlet oxygen by a type II photodynamic process. However, polythiophene compounds also exhibit cytotoxic activity in the absence of light activation. More particularly, we have demonstrated that the polythiophene derivatives of the present invention are effective antitumor agents.
In accordance with this invention there is provided a method for the treatment of cancer which utilizes polythiophene compounds of the general formula: ##STR2## wherein n is 0, 1 or 2, R.sub.1 is H, CHO, CH.sub.2 OH or CH.sub.2 NH.sub.2, and R.sub.2 and R.sub.3 are independently optionally substituted 2- or 3-thienyl. Further in accordance with this invention there are provided novel cytotoxic compounds of the above formula and chemotherapeutic pharmaceutical compositions containing said compounds in anti-tumor effective amounts.
Additional objects, features, and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description of preferred embodiments exemplifying the best mode of the invention as presently perceived.